Zanubrutinib
Zanubrutinib (Brukinsa™)
Generic Name
Zanubrutinib (Brukinsa™)
Mechanism
- Selective irreversible inhibition of BTK, a key kinase in B‑cell receptor (BCR) signaling.
- Binds covalently to the cysteine 481 residue in BTK’s active site, blocking downstream pathways that mediate B‑cell proliferation, survival, migration, and adhesion.
- Minimal off‑target kinase activity relative to ibrutinib, resulting in reduced exposure to ACYP2, EGFR, ITK, and TEC family kinases.
- Consequence: decreased cytokine production, impaired chemotaxis, and induced apoptosis of malignant B‑cells.
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Pharmacokinetics
- Absorption: Rapid oral absorption; peak plasma concentration (Cmax) reached ~2–3 h post‑dose.
- Bioavailability: ~74% with a single dose; food slightly delays Tmax but does not alter AUC significantly.
- Metabolism: Predominantly CYP3A‑mediated; concomitant strong CYP3A inhibitors (e.g., ketoconazole) increase ZA exposure 3‑4×; strong inducers (e.g., rifampin) decrease it by ~75%.
- Elimination: 70–80 % excreted unchanged in feces; ~10–15 % in urine. Terminal half‑life ~21 h, supporting twice‑daily dosing.
- Drug‑Drug Interactions: Avoid ECG‑altering agents that prolong QTc. Valproic acid and ganciclovir increase the risk of myelosuppression.
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Indications
| Indication | FDA‑approved population | Key clinical trial |
| Mantle Cell Lymphoma (MCL) | Relapsed/refractory | iNNOVATE‑MCL |
| Waldenström Macroglobulinemia (WM) | Relapsed/refractory | iNNOVATE‑WM |
| Chronic Lymphocytic Leukemia (CLL) | Relapsed/refractory after ≥1 line of therapy | iNNOVATE‑CLL |
| Marginal Zone Lymphoma (MZL) | Relapsed/refractory | iNNOVATE‑MZL |
| Diffuse Large B‑Cell Lymphoma (DLBCL) | Double‑hit or +p53 mutated | iNNOVATE‑DLBCL |
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Contraindications
- Contraindications:
- Hypersensitivity to zanubrutinib or any excipient.
- Concomitant irreversible BTK inhibitors (ibrutinib, tirabrutinib).
- Warnings:
- Bleeding: Higher risk in patients with platelet dysfunction or on anticoagulation.
- Atrial fibrillation & QTc prolongation: Monitor ECG prior to initiation.
- Immunosuppression: May exacerbate infections (bacterial, CMV).
- Invasive fungal disease: Elevated rates observed on clinical trials.
- Precautions:
- Use caution in hepatic impairment; dose adjustment may be required.
- Plus‑drug interactions with CYP3A milieu; adjust dose accordingly.
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Dosing
| Disease | Dose | Schedule | Administration Tips |
| MCL, WM, CLL, MZL, DLBCL | 160 mg orally | Once daily (QD) or 80 mg BID | Capable of 80 mg BID for patients with higher drug‑drug interaction risk. |
| Special Populations | |||
| Hepatic impairment | *Adjust by 30–50 %* |
• Take with or without food.
• Swallow capsule whole—do not crush or chew.
• If dose missed: take as soon as remembered, but skip if next dose within 4 h.
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Adverse Effects
| Category | Incidence | Typical Management |
| Gastro‑intestinal | Nausea 9–12 %, diarrhoea 5–7 % | Antiemetics, loperamide; consider dose hold for severe diarrhoea. |
| Hematologic | Neutropenia 20 %, thrombocytopenia 8–10 % | CBC q2–4 wk; G‑CSF for neutropenia > Grade 2. |
| Cardiac | Atrial fibrillation 1–2 %, QTc prolongation 4–5 % | Baseline & 3‑month ECG; hold if QTc > 480 ms. |
| Infection | Pneumocystis jirovecii pneumonia (PCP) 3–4 % | PJP prophylaxis per guidelines (TMP‑SMX). |
| Bleeding | Bruising 4–6 % | Avoid NSAIDs; consider ROTEM before invasive procedures. |
| Liver | ALT/AST ↑ > 3× ULN 2–3 % | Monitor LFTs every 4 wk; interrupt if > 5× ULN. |
• Serious: Hypogammaglobulinemia may lead to chronic infections; immunoglobulin replacement is indicated if IgG < 400 mg/dL with recurrent infections.
• Neurologic: Rare cases of headache, dizziness; monitor CNS adverse events.
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Monitoring
| Parameter | Frequency | Rationale |
| CBC with differential | Every 2–4 weeks | Detect cytopenias early |
| CMP (including LFTs) | Every 4 weeks | Hepatotoxicity |
| Electrocardiogram | Baseline, 4 weeks, 6 months | QTc prolongation |
| Serum IgG | Every 3 months | Monitor for hypogammaglobulinemia |
| Infection surveillance | Clinical evaluation | Early detection of opportunistic infection |
| BP/HR | At each visit | Cardiovascular risk profile |
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Clinical Pearls
- Dose Flexibility: The 80 mg BID schedule halves Cmax and reduces peak‑time toxicity, valuable in patients requiring concurrent CYP3A inhibitors or those with high bleeding risk.
- Bleeding Management: Consistently re‑evaluate concomitant antiplatelet agents; consider switching to clopidogrel over aspirin in high‑risk scenarios.
- Infection Prophylaxis: Despite lower overall infection rates vs. ibrutinib, PCP prophylaxis is prudent, especially with concomitant steroids or high‑dose rituximab.
- Cardiac Screening: Even patients with no prior arrhythmia history should undergo baseline ECG; a QTc > 450 ms warrants dose reduction or closer cardiac monitoring.
- Hepatic Dosing: For Child‑Pugh B/C, a 160 mg QD may be considered with close LFT monitoring; avoid in severe cirrhosis (Child‑Pugh C).
- Clinical Trial Data Highlights:
- ORR in relapsed MCL: 63 % (CR 25 %)
- PFS at 12 m: 86 % in WM cohort
- DLBCL double‑hit: 80 % ORR over 1.5 yrs
*These pearls optimize safety, preserve efficacy, and streamline care for patients on zanubrutinib.*